An Evaluation AZD2014 Alone and in Combination With Rituximab in Relapsed/Refractory Diffuse Large B Cell Lymphoma

NCT02752204 | Completed Phase 2 DMC

• 1 other identifier: RG_14-212
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 9

Brief Summary

The aim of this clinical trial is to see if the drug called AZD2014 is effective and safe to use to treat patients with relapsed or refractory Diffuse Large BCell Lymphoma (DLBCL). The trial will also be looking at combining the antibody (Rituximab) with the drug AZD2014 in a small number of patients to see if this can be done without increasing the toxicity. 36 patients will be recruited to the trial. 30 will receive AZD2014 alone and the remaining 6 will receive AZD2014 plus rituximab. AZD2014 will be given as a 125mg tablet that is to be taken twice a day for 2 days out of every 7 (i.e. on days 1 and 2 of every week). Rituximab will be given via IV infusion on day 1 of every 28 days (once every 4 weeks) for a maximum of 6 cycles.

Conditions

Diffuse Large B-Cell Lymphoma

Keywords

Relapsed; Refractory; Lymphoma

Outcome Measures

Primary Outcomes (1)

• Best overall response rate (PR plus CR) (using the Revised Response Criteria for Malignant Lymphoma ) during the first 6 cycles

  Data in relation to this outcome will be collected over the first 6 cycles of therapy - each cycle is 28 days in duration

Secondary Outcomes (7)

• Tolerability rate (based on toxicity assessments using CTCAE v 4.0 criteria) of single agent AZD2014

  Adverse events information will be collected throughout the 18 month recruitment period of the trial and during the one year follow up period

• Tolerability rate of additional toxicities when rituximab is combined with AZD2014 at its standard dose (stage 2 only)

  Adverse events information will be collected from the start of stage 2 during the 18 month recruitment period of the trial and during the one year follow up period

• Best overall response rate post 6 cycles until the end of the trial, assessed using Revised Response Criteria

  Information will be collected from cycle 6 ( each cycle is 28 days) during the 18 month recruitment period of the trial until the end of the trial

• Overall survival (OS) at 1 year

  Information relating to this outcome will be collected up to and including the one year time point

• Progression free survival (PFS) at 1 year

  Information relating to this outcome will be collected up to and including the one year time point

Study Arms (2)

Stage 1

OTHER

AZD 2014 oral tablets will be given to patients

Drug: AZD 2014

Stage 2

OTHER

AZD 2014 oral tablets and rituximab infusion will be given to patients

Drug: AZD 2014; Drug: Rituximab

Interventions

AZD 2014 DRUG

AZD2014 125mg BD - 2 days on 5 days off in a 28 day cycle

Also known as: Vistusertib

Stage 1; Stage 2

Rituximab DRUG

Rituximab 375mg/m2 will be administered intravenously on day 1 of a 28 day cycle for a total of 6 cycles.

Also known as: Mabthera

Stage 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) relapsing after at least 1 course of potentially curative, anti-CD20 antibody containing regimen (e.g. RCHOP, GCHOP, RGCVP). High grade transformation from low grade lymphoma (e.g. follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukaemia) is permitted. Patients must have relapsed post-ASCT or be considered not suitable for ASCT.
• Tissue biopsy (or bone marrow trephine if no other tissue available) confirming histology within 3 months of enrolment.
• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
• Aged at least 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Females should be using adequate contraceptive measures (as described in the protocol, different for patient receiving rituximab), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
• Post-menopausal defined as amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• Male patients should be willing to use barrier contraception (i.e. condoms) as described in the protocol, (different for patient receiving rituximab\*)
• Ability to swallow and retain oral medication
• CT measurable disease with at least 1 lesion having short axis ≥ 1.5cm or splenomegaly ≥ 14cm in cranio-caudal length attributable to relapsed lymphoma
• Patients must have negative virology for HIV, hepatitis B and hepatitis C prior to trial entry. Patients with an isolated anti-hepatitis B sAg antibody may be entered as this indicates previous vaccination.. These patients MUST have HBV DNA tested.

You may not qualify if:

• Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 14 days of registration (not including palliative radiotherapy at focal sites). Corticosteroids are permitted during screening but should be weaned down to a maximum dose of prednisolone 10mg daily (or equivalent) by day 1 of cycle 1.
• \- With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.0) Grade 2 at the time of registration.
• Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study.
• Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout periods before the first dose of study treatment.
• Exposure to potent or moderate inhibitors or inducers of CYP2C8 if taken within the stated washout periods before the first dose of study treatment.
• Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period (a minimum of 5 x the reported terminal elimination half-life of each drug) before the first dose of study treatment.
• Previous treatment with any first generation mTORC1 inhibitors (rapamycin, sirolimus, temsirolimus, everolimus) or any dual mTORC1/2 inhibitors (e.g. AZD2014, AZD8055).
• Patients who have experienced intolerable AEs prejudged by the treating Investigator due to other mTORC1 or mTORC1/2 inhibitors, PI3 kinase inhibitors, or AKT inhibitors.
• Patients with proven central nervous system (CNS) involvement.
• As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases (e.g., severe hepatic impairment, interstitial lung disease (e.g.bilateral, diffuse, parenchymal lung disease), uncontrolled chronic renal diseases (e.g. glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis) or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension, active bleeding diatheses or active infection. Screening for chronic conditions is not required.
• Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months:
• coronary artery bypass graft
• angioplasty
• vascular stent
• myocardial infarction

Sponsors & Collaborators

• University of Birmingham: lead
• Bloodwise: collaborator
• AstraZeneca: collaborator
• Cancer Research UK: collaborator

Study Sites (9)

Aberdeen Royal Infirmary

Aberdeen, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, L7 8XP, United Kingdom

Location

University College London Hospitals

London, NW1 2PG, United Kingdom

Location

Guys Hospital

London, SE1 9RT, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Norfolk & Norwich University Hospitals NHS Foundation Trust

Norwich, NR4 7UY, United Kingdom

Location

The Churchill Hospital

Oxford, OX3 7LE, United Kingdom

Location

Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, S016 6YD, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Recurrence; Lymphoma

Interventions

vistusertib; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Graham Collins, MBBS DPhil

  The Churchill Hospital, Oxford, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2016
• First Posted: April 26, 2016
• Study Start: October 1, 2015
• Primary Completion: September 7, 2017
• Study Completion: February 6, 2020
• Last Updated: November 5, 2020

Record last verified: 2020-11

Locations

GB (9)